A blood test for early detection of cancer would provide a valuable, additional means for screening the population at risk. Blood-based biomarkers for monitoring cancer could enhance care by earlier identification of subjects at risk of recurrence, better prognostic assessment, and potentially, improvements in survival or quality of life due to earlier implementation of alternative therapy. Thus, a liquid biopsy for early detection and for non-invasive assessment of tumor and tumor characteristics during treatment would represent a significant medical advance. Circulating tumor DNA (ctDNA) are small fragments of nucleic acid that originate from apoptotic or necrotic tumor cell turnover. Characteristic of the malignant process, ctDNA can be assessed in plasma, and offers the potential of a sensitive and specific biomarker for a host of applications including diagnosis or early detection of tumors, prognostic information on disease-free or overall survival, and predictive information on resistance and probability of lack of response to treatment. Previous ctDNA studies have been implemented by identifying characteristic mutations in the primary tumor and subsequently interrogating plasma DNA from the same patient for the presence of those mutations. The next step in evaluating ctDNA as a screening modality is to construct a panel of mutations amenable to detection in plasma (a PlasmaSeq panel) to assess the sensitivity and specificity of plasma ctDNA in identifying cancer without prior knowledge of which mutations are present in the tumor of the patient whose plasma is assayed. In Aim 1, we will prospectively recruit patients with colorectal cancer (CRC), disease-free controls, and subjects with adenomas prior to definitive surgical or endoscopic treatment and systematically evaluate a PlasmaSeq panel to explore the utility of ctDNA as a marker for early detection. Previous studies suggest that ctDNA can be used to monitor cancer in subjects under treatment or at risk for recurrent disease. In Aim 2, we will recruit newly diagnosed stage III CRC patients, determine their tumor mutational profile, and systematically collect high volume (>10 ml), serial plasma specimens every 3 months for up to 4 years for ctDNA and concurrent CEA measurement. Clinical outcome and survival will be tracked and parameters of ctDNA assessment, including absolute level, velocity of change, and degree of fluctuation will be evaluated in relation to clinical outcome, stratified by tumor stage classification (stage IIIA-III). The resulting data will permit assessment of ctDNA as a prognostic marker for disease-free and overall survival. This research will further advance study on the use of ctDNA in early detection and monitoring of CRC. ctDNA testing is also applicable to many other cancers. Thus, advancement in this technology is potentially of great impact to cancer care.